Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels through endothelial cell proliferation and migration with remodeling of the extracellular matrix. It is a normal process in organ development and differentiation during embryogenesis, in wound healing, and in the uterus and ovary. It is also involved in pathogenic disorders such as diabetic retinopathy, diabetic macular edema, age-related macular degeneration, ischemic heart disorders, rheumatoid arthritis, psoriasis, tumorigenesis and tumor growth.
According to The Angiogenesis Foundation, at least 184-million patients in Western nations alone could benefit from some form of anti-angiogenic therapy, and at least 314 million from some form of pro-angiogenic therapy. For example, anti-angiogenic therapy applies to all solid tumors (lung, breast, prostate, colon cancer etc.). The market for anti-angiogenic therapies is huge as implied by first quarter 2007 financial reports of Ranibizumab™, which treats age-related macular degeneration. It has already been a pharmaceutical blockbuster in 2007 with estimated annual revenues of over 1 billion dollars.
The mechanism of angiogenesis is not well understood; however, several factors have been identified to be involved in angiogenesis as angiogenesis stimulators and inhibitors. Some of the angiogenic factors are fibroblast growth factor, transforming growth factor-α, transforming growth factor-β, angiogenin, interleukin-8, platelet-derived growth factor, vascular endothelial growth factor (VEGF). Among them, VEGF is considered to be the most important cytokine in pathological angiogenesis.
Several potentially effective anti-angiogenic agents have been developed and investigated in animal, epidemiological and clinical studies (Kyselova et al., 2004). They could be classified as inhibitors of VEGF, antagonists of vascular endothelial growth factor receptors (VEGFRs), and VEGFR tyrosine kinase inhibitors. Inhibitors of VEGF could be humanized monoclonal antibodies of VEGF and VEGF trap—the soluble truncated form of VEGFR. VEGFRs antagonists could be humanized monoclonal antibodies or small-molecule inhibitors. Several small-molecule inhibitors of VEGFR tyrosine kinase inhibitors have been developed, of which some are selective to VEGFR2 and/or other VEGFRs and some less selectively target cancer growth. In addition, dopamine D2 receptor agonists were reported as anti-angiogenic agents with suggested mechanism of internalization of surface VEGFR-2 (Basu et al., 2001). The development of small molecule inhibitors of angiogenesis is regarded as an important therapeutic area as it offers potentially long-term treatment, with significantly fewer side effects than traditional chemotherapeutic treatment regimes.
Three specific inhibitors of VEGF are in the market: Bevacizumab™ (Genentech & Roche), Ranibizumab™ (Genentech & Novartis), and Pegaptanib™ (Pfizer). However, all of them are associated with high cost, thus the development of low cost anti-angiogenic drugs is highly desired.
We previously reported on the potent anti-glycation activity of catechols, dopamines and adrenalines (Yeboah et al., 2005), and its application to prevent cataract (Mullick & Konishi, 2007). Drug repositioning of adrenalines has advantages for topical ocular applications, as dipivefrin, a prodrug of (R,S)-adrenaline, is a commercial eye drop drug to treat glaucoma. Thus, we developed eye drops to prevent diabetic retinopathy based on adrenalines.
One of the lead compounds is (S)-isoproterenol. Systemic (S)-isoproterenol is 200 to 1600 times less effective than (R)-isoproterenol on blood pressure, rate of perfused heart, and uterine relaxation, demonstrating weak activity as β-adrenoceptor agonist (Lands et al., 1954). (S)-isoproterenol is an antagonist of α-adrenergic receptors as it shows antinociceptive action, where nociceptive action is typically caused by agonists of α2-adrenergic receptor (Bentley and Starr, 1986).
(S)-isoproterenol is considered to be safe for humans. The acute intravenous toxicity of (S)-isoproterenol in mice is approximately half of that of (R)-isoproterenol, i.e., LD50 values of (S)-isoproterenol and (R)-isoproterenol were 113±5 mg/kg and 57±2 mg/kg, respectively (Lands, et al., 1954). Furthermore, (S)-isoproterenol is an inactive ingredient of commercial bronchodilator and topical anti-allergic drugs of (R,S)-isoproterenol. Some side effects of (S)-isoproterenol have been reported only at extremely high concentrations. Topically applied 10% (S)-isoproterenol in humans caused brief mild conjunctival hyperemia and irritation, and 20% (S)-isoproterenol eye drop produced marked conjunctival hyperemia and mild miosis that persisted for several hours (Kass at al., 1976). However, no systemic effects of heart rate, blood pressure, and hematologic or serum chemistry values as well as no change at necropsy were observed in rabbit even with 17.6% (S)-isoproterenol eye drop (Seidehamel et al., 1975). Also a large intravenous dose of (S)-isoproterenol appeared to have only slight and transient effects on blood pressure and pulse rate (Kass et al., 1976).
One of the prodrug forms of (S)-isoproterenol is (S)-isoproterenol dipivalate. Although no systemic study of (S)-isoproterenol dipivalate has been reported, the racemic mixture (R,S)-isoproterenol dipivalate (58 μg/kg) was intravenously injected in dogs. It produced the same responses as those of (R,S)-isoproterenol, i.e., large increase in heart rate and in cardiac output, marked decrease in total peripheral resistance, decrease in aortic pressure, in central venous pressure, and in left atrial pressure, and no significant change in pulmonary vascular resistance. These responses began slower and lasted longer than those of (R,S)-isoproterenol. The results suggest that (R,S)-isoproterenol dipivalate is inert and exerts the effects after it is hydrolyzed to (R,S)-isoproterenol (Wang, et al., 1977).